The present invention relates to a way of enhancing the pharmacological effectiveness of the hormone insulin.
There now exist a number of non-insulin containing hypoglycemic agents and these have recently been reviewed (Asmal, et al., Drugs, 28, 62-78 (1984) and Wolf, et al., Diabetologia, 22, 456-463 (1982)). The Sulfonylurea drugs stimulate insulin secretion from the pancreas and exert other as yet undetermined peripheral effects; the biguanides inhibit gluconeogenesis, intestinal glucose absorption and mitochondrial oxidation; 2-bromopalmitate, .omega.-methyl 2-tetradecylglycerate, B807-27 and acyl aminocarnitines interfere with carnitine palmitoyl-transferase I enzyme which inhibits long-chain fatty acid oxidation.
Insulin is a polypeptide hormone of molecular weight 6,000 daltons which is secreted from the pancreas and is involved in the maintenance of glucose homeostasis.
The diabetic patient must be treated with insulin or other hypoglycemic agents when insulin is either not produced (Type I diabetes) or inappropriately utilized (Type II diabetes) in order to deter the many harmful effects of elevated blood glucose levels and disturbed metabolism. It is clearly recognized that a variety of pathological defects may lead to the diabetic state. A review of these and the current strategies for treatment were recently reported (Diabetes Dialogue, Am. J. Med., 79 (Suppl 2B), 1-44 (1985)).
Many diabetics require insulin injections one or more times a day to maintain their blood glucose levels within normal limits after meals.
Because injected insulin is quickly degraded by tissue proteinases, its effectiveness in lowering blood sugar is temporary. The destruction of insulin by the protease insulinase after injection occurs with a t.sub.1/2 of approximately 40 minutes and, because of this short duration of action, many methods have been sought to inhibit this proteolytic inactivation of insulin in order to prolong its effectiveness. It has been reported in the literature that one such agent to inhibit insulinase in vitro is the antibiotic bacitracin.
Bacitracin is a polypeptide antibiotic which has been found useful as an antimicrobial agent in humans and as a growth promoter in animals. The antimicrobial properties to commercial bacitracin resides mainly in one traction, bacitracin A. It works best against gram-positive bacteria by disturbing their membrane function, cell wall synthesis and protein metabolism.
The most widely used food additives for growth promotion are the zinc bacitracin and bacitracin methyldisalicylate forms of this antibrotic. While it is generally accepted that the addition of low levels of antibiotics to feeds can improve animal growth and product, the mechanism of action is unknown (Froyshov, Drugs and Pharmaceutical Science, Chapt. 24, 665-694 (1984)).
It has been known for many years that the commercial preparation is a mixture of at least 20 different compounds with bacitracins A and F representing respectively 65-70% and 15-20% of the total content (Tsuji, et al., J. Chromatog., 99, 597-608 (1974)). In addition to its antibiotic properties, the commercial preparation of bacitracin has been shown to be capable of inhibiting the degradation of insulin in a variety of in vitro experimental situations such as with isolated rat hepatocytes and adipocytes (Duckworth, et al., Endocrinology, 108, 1142-1147 (1981), Roth, et al., Biochem. Biophys. Res. Commun., 98, 431-438 (1981) and Peavy, et al., Diabetes, 34, 217-221 (1985)). Thus bacitracin was shown to potentiate the action of insulin on glucose utilization.